Process fgh preparing j-pyridinols



United States Patent fifice 2,806,852 Patented Sept. 17, 1957 PRUCESS Fill? PREPARENG 3 PYRlDINOLS- Niels Konrad Friedrich Wilhelm Clanson-Kaas, Haifa, Israel, and Niels Elming, Copenhagen, Denmark- No'Drawing. Application November 29, 1954,

erial No. 471,896.-

Claims priority, application DenmarkNovemher 30,.1953

8 Claims. (Cl. 260-297) The present invention relates to the preparation of 3- pyridinols.

3-pyridinol and various. 2-alkyl-3-pyridinols" havealready been described in earlier publications,; but the present invention makes it possible to producethese compounds in a simpler-manner andwith-better yieIdsLthaIr heretofore.

According to the invention, 3-pyridi'nols are produced by oxidizing to produce 2,5 dialkoxy furans, a compound.

of the formula NHz in'which R is hydrogen oralkyl, forinstanceamethyl, theamino group being, if desired, protected byy-conversionto the corresponding acylate, carbamate" or mono.- or. diureid, whereupon the product is subjected;-.if desired, after at preceding saponification, tohydrolysis by being stored or heated in an acid or neutral medium, a pyridine ring being formed due to condensation.

According to a preferred embodiment ofrtheinvention, the compound of the above formula-has =its=amino-.group protected as mentioned above andiszoxidized in. a-.solution in an. alcohol by electrolysis in the presence of an electrolyte which is soluble in the alcohol employed, for instance, ammonium bromide, lithium bromide, a-mixture ofthese two, sulfuric acid, boron trifluorideor an organic boron trifluoride complex such as boron trifluoride'etherate or borontrifiuoride acetic" acid complex, a nitrate,a.th'iocyanate or a formate. The electrolyteunay alsob'e-au organic halogen salt such as' for instance, morpholine hydrobromide.

The alcohol used in the electrolysis. is preferably methe anol, as the aforesaid electrolytes arereadily soluble-in methanol and the electrolysis runs smoothlyand at. a satisfactory-rate when carried out-in thisz-alcohoh. However, good results are obtained alsowithfor instance, ethanol, Z-ethoxy ethanol, etc.

The electrolysis is carried out in amanner. known per se; for. instance. using the apparatus; descrihedint Acta Chem. Scand. 6, 1952, page 531, or usiugItheva paratnS described inActa Chem. Scand; 7,.1953', .page 234 The electrolysis should. be: carried" out at. aztempera: ture of between C. and-30 C., preferably'atiabout --1'i C. As arule', a terminalvoltage-ofabout31o. 20 volts is suflicient. The currentisn'engtlr; may vary wide limits depending'on' the desired oxidation rate; This is due to the fact that the starting materials. used accorde in'g to-the invention are comparatively stable: However, the current strength should preferablyr'lie within'thetrange of fromOl to 10 amperes.

According to another embodiment ofthe invention, the compound of the'above' formula, ifdesired; protected as stat'edabove, is oxidized for a few minutes to ahalf an hour or more, with chlorine or bromine-in an anhydrous alcohol, preferably methanol, at a low/temperature, for

instance, at -10 C. to 30 C. and preferably at about -20 'C., with a simultaneous or subsequent addition of a neutralizing agent such as'potassium acetate or sodium acetate.

After havingbeen oxidized in either of the above-described ways the oxidation product may be converted to the desired 3-pyridinolseither by alkaline saponification in a manner known per se, with subsequent hydrolysis, or by hydrolysis alone. Ithas been found that such oxidation products in which'the amino group is protected by an acyl group, such as an acetyl group, should preferably be converted to 3-pyridinol by the first-mentioned process i. e., by saponification and hydrolysis, preferably in arr acid medium. However, the hydrolysis may also be carried out in a neutral medium at a higher temperature; On the other hand, it has been found that oxidation products having their amino group protected by conversion to thecarbamate, or monoor diureid, will give 3-pyridinols in especially good yields when subjected to direct hydrolysis in an acid medium; This-reaction is-preferably carried out by boiling with a dilute inorganic acid, for instance, hydrochloric acid, sulfuric acid, hydrobromic acid etc., preferably atan acidconcentration of 0.5-nto 2-n.

After said saponificationand hydrolysis, or hydrolysis alone, the reaction mixture is evaporated to dryness. Inthe first case, pure 3-pyridinol hydrochloride is obtained, while in thelatter case the free 3-pyridinol is obtained by an addition of, for instance, potassium or sodium carbonate, the 3 pyridinol thenbeing isolated by extraction with a suitable-solvent; such' as, for instance; ether.

According to one embodiment of the invention, the oxidation may also be'achieveddirectly by rapidly supplying'chlorineor-bromine toan aqueous alcohol, preferably methanoliorethanol, containing Water-in an amount of 20-90%, preferably 40-80'%-, this step being carried out at alow temperature, a suitable range being from 10 C. to C. and preferably from -20 C. to -80"- C. fora short period of'time (about 5-30 minutes).- More Water (about 3060%, calculated-on-the volume of the reaction mixture) is preferably added, and the mixture is again boiled for a short time (l030minutes),- whereupon the 3 pyridinol is isolated. The isolation may be carried out by precipitation with, for instance, potassium or'sodiumcarbonate, whereupon the precipitated 3 pyridinol is either filtered otf or recovered by extraction, for instance, with ether.

According to still another embodiment of the invention, the starting material need'not be a-furanderivative substitutedin the 2-position by an a-arninoalkyl group-but may be substituted in this position by a group which after theoxidation" of the fund derivative to a- 2,5-dialkoxy-2,5-dihydrofuranis converted to an a-aminoalkyl group. This way of' carrying out the steps in inverse order is within the scope of the present invention.

The inventionis'illustrated bythe following examples:

Example' 11-6196 girls. of 2'-acetamidomethyl-2,5-dimethoxy-2,5-dihydrofuran- (produced as described in Acts. Chem. Scand; 6 l952), page-667) are refluxed for 16 hours with' mls. of 3-N sodium hydroxide solution. Thereaction mixture'is then continuously extracted with ether. The ether extract yields 4.72 gms. of Z-amiriomethyl-2,5 dimethoxy-2,5 dihydrofuran which are then refiuxedfor'IS minutesWith 54 mils. of l-Nhydrochloric acid.- The resulting solution isevaporated in vacuo to dryness, and the residue'isdissolvedin ethanol. Crystallization gives-3.63 gms. of- S-pyridinol hydrochloride (M. P. -1 07C.), corresponding to a 93% yield obtained by the hydrolysis under acidlconditions.

Example 2. 4.04 gms. of 2-acetamidomethyl-2,5-dimethoxy-Lfidihydrofuran arerefluxed for 15 minutes with 22 mls. of lN hydrochloric acid whereupon the resulting solution isevaporated in vacuo to dryness. The

Example 3.19.4 gms. of furfurylamine and 6.6 gms.

of urea are refluxed for one hour. The crystalline reaction product is dissolved in a solution of 5.0 gms. ammonium bromide in 260 mls. of methanol whereupon the solution is electrolysed, for instance, in the manner as de scribed in the British Patent No. 682,736, 11.9 amperehours being required. The electrolysate is poured into a solution of sodium methylate (1.2 g. of sodium in 20 ml. of methanol) and is evaporated in vacuo. The residue is refluxed for 15 minutes with 240 mls. of lN hydrochloric acid and is then evaporated to dryness. The residue obtained is admixed with 22 gms. of potassium carbonate, whereupon water is added. The 3-py1idinol is liberated in an amount of 16.1 gms. which corresponds to 85% of the theoretical yield.

Example 4.15.6 gms. of 2-acetylfuranoxime are dissolved in 200 mls. of anhydrous ethanol to which'26.5 mls. of acetylchloride already have been added. The solution is shaken for four hours with 6.5 gms. of palladium charcoal (10%) under gaseous hydrogen at a pressure of 15 atmospheres. After filtration, the solvent is distilled in vacuo, the residue is adjusted to alkaline reaction, and is then extracted with ether. The ether extract yields 6.5 gms. of Z-(a-amincaethyD-fman which is a colourless liquid; boiling point: 148-149 C., and n =l.4748. a

6.12 gms. of 2-(a-aminoethyl)-furan are dissolved, with cooling, in 9.5 mls. of -N hydrochloricacid to which is added a solution of 3.45 gms. urea in 16 mls. water, whereupon the mixture is refluxed for 16 hours. Upon cooling, filtration, washing twice with water and drying, 4.24 gms. (50%) of Z-(a-uIeidoethyD-furan are obtained. On recrystallization from ethyl acetate, the product is obtained in a yield of 2.96 gms. of white crystals melting at 114116 C.

340 milligrams of Z-(a-ureidOethyD-furan are dissolved in a solution of 150 mgs. of ammonium bromide in mls. of methanol whereupon the mixture is electrolyzed in the apparatus described in Acta Chem. Scand. 7 (1953), page 234, 0.13 ampere-hour being required. After the electrolysis, the mixture is poured into a solution of sodium methylate (produced from 37 mgs. of sodium and 4 mls. of methanol). Then the product is evaporated in vacuo, the residue is refluxed for minutes with 22 mls. of l-N hydrochloric acid, and the resulting product is treated further as in Example 1. Upon purification 200 mgs. (62%) of 2-methyl-3 pyridinol hydrochloride are obtained;melting point: 225-227" C.

Example 5 .2-(carbomethoxyarnidomethyl) furan is produced from furfuryl amine according to the method described in Org. Syntheses, collective volume 2 (1943), page 278. The substance is a colorless liquid; boiling point: 122123 C. at 10 mm. of mercury, and n =1.4-85l.

31.0 gms. of 2-(carbomethoxyamidomethyl)-furan are electrolyzed according to the method described in Acta Chem. Scand. 6 (1952), page 667, 11.8 ampere-hours being required, representing 110% of the theoretical consumption. In this manner 38.7 gms. (89%) of 2,5 dimethoxy 2 carbomethoxyamidomethyl 2,5 dihydrofuran are obtained as a colorless liquid; boiling point at 0.2 mm. of mercury: 104107 C., and having n 25=1.4652. Then 4.34 gms. of this compound are refluxed with 22 mls. of 1-N hydrochloric acid, and upon a further treatment in the same manner as in Example 3, there will be obtained 1.45 gms. (76%) of 3-pyridinol.

Example 6.12.5 gms. of 2-acetylfuranoxime are hydrogenated as described in Example 4. The reaction mixture is filtered and evaporated in vacuo to dryness. The evaporation residue is dissolved in m1s.'of water, extracted with ether and reacted with'9.5 gms. of chloroforrnic methylester (CICOOCI-Is) as jdescribed in' Org.

Syntheses, collective volume 2 (1943), page 278. In this manner 9.2 gms. (54%) of 2-(a-carbomethoxyamidoethyl)-furan are obtained as a colorless liquid; boiling point: 7275 C. at 0.1 mm. of mercury, and n =1.4805. Then 11.6 gms. of this compound are electrolyzed according to the method described in Acta Chem. Scand. 6 (1952), page 657, 4.1 ampere-hours being required (110% of the theoretical consumption). In this manner 13.8 gms. (88%) of 2,5-dimethoxy-2-(acarbomethoxyamidoethyl)-2,5-dihydrofuran are obtained as a colorless liquid; boiling point: 98102 C. at 0.2 mm. of mercury, and n =1.4649. Then 2.31 gms. of this compound are refluxed for 1.5 hours with 100 mls. of 1N hydrochloric acid, whereupon the mixture is evaporated, and the residue further treated and purified as described in Example 1. The yield obtained is 1.05 gms. (72%) of 2-methyl-3-pyridinol hydrochloride.

Example 7.12.5 gms. of 2-acetylfuranoxime and 30 mls. of acetic anhydride are shaken with 1.6 gms. of Raney nickel under gaseous hydrogen at a pressure of 100 atmospheres and at 70-80 C. On distillation of the reaction mixture 9.8 gms. (64%) of Z-(a-acetamidq ethyD-furan are obtained as a light yellow liquid; boiling point: 86-89 C. at 0.1 mm. of mercury, and n =1.4922. This compound may also be obtained by acetylation of 2-(m-aminoethyl) -furan, the production of which is described in Example 4.

2.00 gms. of Z-(a-acetamidoethyD-fumn, 0.30 gm. of ammonium bromide and 20 mls. of methanol are electrolyzed by the method described in Acta Chem. Scand. 7 (1953), page 234, 0.77 ampere-hour being required (110% of the theoretical consumption). In this manner 2.47 gms. (88%) of 2,5-dimethoxy-2-(a-acetamidoethyl)- 2,5-dihydrofuran are obtained as a colorless liquid; boiling point: 110115 C. at 0.1 mm. of mercury, and n =l.4739. Then 2.15 gms. of. this compound are s'aponified in an alkaline medium as described in Example 1, there thus being obtained 1.39 gms. of 2,5-dimethoxy-2- a-aminoethyl) -2,5-dihydrofuran as a colorless liquid; boiling point: 92 C. at 12 mm. of mercury, and n =1.4565. Then 1.10 gms. of this compound is hydrolyzed and condensed in an acid medium, whereupon the product is further treated as described in Example 1. of 2-rnethyl-3-pyridinol hydrochloride.

Example 8.--2.78 gms. (0.020 mol) of 2-(a-acetamidoethyl)- furan (prepared by acylation of furfurylamine) and 4.00 gms. (0.041 mol) of potassium acetate were dissolved in 24 mls. of anhydrous methanol. 7 The mixture was cooled to 20 C., and a solution of 1.00 ml. (0.020 mol) of bromine in 20 mls. of anhydrous methanol was added at 20 C. during 5 minutes, with efficient stirring. The stirring was continued for 10 minutes and the mixture evaporated in vacuo. 200 mls. of anhydrous ether were added to the residue, the potassium bromide was removed by filtration, and the filtrate was distilled in vacuo. The yield was 3.21 gms. (80%) of 2,5 dimethoxy 2 (u acetamidoethyl) 2,5 dihydrofuran, B. P.o,1 -140 C. The product crystallized partly on standing.

C5H6ON(COCH3)(OCH3)2. Calc.: C, 53.7; H, 7.5; N, 7.0; OCHs, 30.9; COCHs, 21.4. Found: C, 53.9; H, 7.7; N, 7.3; OCH3, 30.7; COCH3, 21.3.

The resulting product was then converted to 3-pyridinol as described in the Examples 1 and 2.

Example 9.0.97 gm. (0.010 mol) of furfurylamine and 0.33 gm. (0.0055 mol) of urea were mixed and refluxed (1 hour) in an 'oil bath (-200 C.). The reaction product was dissolved in a solution of 2.00 gms. (0.0204 mol) of potassium acetate in 13 mls. of anhy drous methanol, and the mixture was cooled to 20 C. A solution of 0.50 ml. (0.010 mol) bromine in 10 mls. of anhydrous methanol was added at 20 C. during 5 minutes, with el'ficient stirring. The stirring was con-- tinueclfor 10 minutes, and the mixture was evaporated The yield obtained is 0.88 gm.

12 mls. of 1-Nhydrochloric acid were'added, and the-mixture was refluxed for- 15 minutes. The 3- pyridinol'was isolatedas described in Example 3. The yield was'0.65 gm. (68%), M. P. 122-124 C. (Hershberg apparatus, corr.).

Example 10.9.7 gms; (0.1'mol) of-furfurylamine were' dissolved in 50-"mls. water and 40 mls; methanol: Then 4.28 mls. chlorine, saturated at 80" C. (;1'mol) was passed into the solution at 60 C. to 80 C. for minutes. The light'yellow semisolid reaction mixture was heated to boiling. 20 mls. of water were added and the dark red solution evaporated to a volume of about 50 mls. After co'oling, 13.8 gms. (0.1- mol) of anhydrous potassium carbonate were added, a'brown precipitate of impure 3-pyridinol was removed by filtration, washedo'nce"withwaterand dried. The yield was 4.94 gms. from which 425 gms. (45%) of3-pyridinol (colorless crystals) were obtainedby' sublimation.

Example 1J.9.7 gms. (0.1 mol) of furfurylamine were dissolved in 70 mls. water and 30 mls. methanol. A solution of 5.0 mls. (0.1 mol) of bromine in 50 mls. methanol, cooled to 80 C., was added at -50 C. to -80 C. during 1 minute. The light yellow reaction mixture was heated to 0 C., 50 mls. of water were added, and the methanol was removed in vacuo. The remaining aqueous solution was refluxed for 15 minutes whereby the solution became dark red. The solution was evaporated to dryness in vacuo. The dark residue was dissolved in 50 mls. of methanol. 500 mls. of ether were added, and a precipitate of 3-pyridinol hydrobromide was removed by filtration and dried (13.2 gms.). 70 mls. water and 13 gms. potassium carbonate were added, and the mixture was continuously extracted with ether. In this manner 6.6 gms. (70%) of pyridinol (almost white crystals) were obtained.

Example 12.9.7 gms. (0.1 mol) of furfurylamine were dissolved in 100 mls. water, and a cooled solution of 5.0 mls. (0.1 mol) of bromine in 20 mls. ethanol was added during seconds with stirring at -20 C. The

in vacuo.

almost colorless reaction mixture was heated to boiling and evaporated to a volume of about 50 mls. After cooling, 13.8 gms. (0.1 mol) of potassium carbonate were added to the dark red solution. A brown precipitate of impure 3-pyridinol was removed by filtration, washed once with water and dried. The yield was 8.0 gms. from which 6.3 gms. (66%) of 3-py1idinol (colorless crystals) were obtained by sublimation.

Example 13.10.5 gms. of Z-carbomethoxy-S-isopropylfuran are dissolved in 45 mls. of methanol to which 0.375 gm. of concentrated sulfuric acid have been added. The solution is then electrolyzed in the apparatus described in Acta Chem. Scand. 7 (1953), page 234. 4.20 ampere-hours being required (125% of the theoretical consumption). After the electrolysis, the reaction mixture is poured into sodium methylate (175 mgs. of sodium in 7 mls. of methanol), whereupon the methanol is evaporated in vacuo and to the residue are added 50 mls. of dry ether. After filtration and distillation 12.5 gms. (86%) of 2,5-di-methoxy-Z-carbomethoxy-5-isopropyl-2,5-dihydrofurau are obtained as a colorless liquid; boiling point: 71 75 C. at 0.1 mm. of mercury, and n =1.4498. Then 3.45 gms. of this compound are mixed at 50 C. with a solution of 2.2 mls. ammonia (measured at 80 C.) and 0.3 ml. of water in 6 mls. of methanol. The resulting solution is allowed to stand for 7 days at room temperature and is then evaporated in vacuo. The residue is dissolved in dry ether whereupon the solution is evaporated to dryness, finally at 0.1 mm. of mercury, to remove traces of water and methanol. The residue obtained is dissolved in 90 mls. of ether, and the solution is added dropwise, with stirring, to a mixture of 0.97 gm. of lithium aluminum hydride in 60 mls. of ether. After having been stirred for 20 hours at room temperature, the mixture is cooled to 20 C., whereupon 20 mls. of water and then 25 mls. of 25% sodium hydroxide solution are 'added 'dropwise. extracted continuously with ether. dried with magnesium sulfate and then distilled, there thus being obtained 2.13 gms (71%) of 2,5-dimethoxy-2- amino-methyl 5 isopropyl 2,5 dihydrofurau as a colorless liquid; boiling point: 121-126 C. at 13 -12 mm. of mercury, and n 1.4625. Then 1.50 gms. of

this compound-is refluxed 'for 15 minutes with 17' mls.: of

lN hydrochloric-acid, whereupon'theproduct is evapo rated to drynessin vacuo. The evaporation residue'is dissolved in 10 mls. of water, andthen' 1.0 g; of potassium carbonate are added.-- The-mixture isextracted continuously with ether. Theether extract yields 0.71 gm: (69%) of 6-isopropyl 3pyridinol melting at l55-157 C.

While the invention hasbeendescribedand exemplified' with respect to furan starting'materials, which are not substituted in the 3- and 4-position, it is to be understood":

that in its broader aspects, the starting material maycornprise; after oxidation- 0f the' corresponding.2-(maminoz.

alkyl)-furans, a furan compound havingv thegeneral formula:

a R2 R10 0R1 R4 0 CHR where R represents hydrogen or an alkyl group, including a cycloalkyl group, R1 represents alkyl or cycloalkyl groups of not more than 6 carbon atoms, and R2, R3 and R4, which may be alike or different, represent hydrogen or substituents, which are not attacked by the said oxidation, e. g. alkyl, substituted alkyl, including hydroxyalkyl and acyloxyalkyl, aryl, substituted aryl, aralkyl, carboxyl, esterified carboxyl, carbamidoalkyl, halogen and nitro groups. Preferably R represents methyl groups.

The process then proceeds according to the following scheme of reaction:

R; R, R10 l on.

l NH:

in which R, R1, R2, R3 and R4 have the meanings assigned immediately above.

The invention further comprises a method in which the above reaction is one of the steps, the starting material being an amide of the general formula:

wherein R5 is a radical of the general formula:

R: R2 R1 0 0 R1 R. 0 na-NH- The mixture 1 is. The ether extracts are tions to produce a 2,5-dia1koxy furan, a compound of in which R is selected from the group consisting of a hydrogen atom and an alkyl group and hydrolyzing the resulting product at a pH at least as low as 7 to form a pyridine ring by condensation.

2. The method of claim 1 in which said compound has the amino group protected by conversion to a derivative selected from the group consisting of acylates, carbamates, monoureids and diureids.

3. The method of claim 1 in which the alcohol is methanol.

'4. The process of claim 1 in which the oxidation is carried out electrolytically in the presence of an electrolytetsoluble in the alcohol.

g 5. The process of claim 4 in which the oxidation is carried out at a temperature between 0 C. and -30 C. 6. The process of claim 2 in which said oxidation is carried out with a halogen selected from the group con- 7 sisting of chlorine and bromine in anhydrous methanol.

7. The process of claim 1 in which the oxidation is carried out with chlorine or bromine in an aqueous alcohol solution. i

8. The 'process of claim 7 in which said alcohol is selected from a member of the group consisting of ethanol and methanol.

References Cited in the file of this patent UNITED STATES PATENTS 2,527,421 Hofm'ann Oct. 24, 1950 2,636,882 Dunlop et a1 Apr. 28, 1953 2,672,461 Dunlop Mar. 16, 1954' 

1. A METHOD OF PRODUCING 3-PYRIDINOLS COMPRISING REACTING WITH AN ALIPHATIC ALCOHOL UNDER OXIDIZING CONDITIONS TO PRODUCE A 2,5-DIALKOXY FURAN, A COMPOUND OF THE FORMULA 